The nucleolytic processing (resection) of a DNA double-strand break (DSB) is a critical step to repair the lesion by homologous recombination (HR). PARylation, which is the attachment of poly(ADP-ribose) (PAR) units to specific targets by PAR polymerases (PARPs), regulates many steps of HR, including resection. Here, we show that preventing PARylation of the oncosuppressor BRCA1 induces hyper-resection of DSBs through BRCA2 and the EXO1 nuclease. Upon expression of the unPARylatable variant of BRCA1, we observe a reduced 53BP1-RIF1 barrier for resection accompanied by an increase in the recruitment of the RAD51 recombinase. Similar results are observed when cells are treated with the clinically approved PARP inhibitor olaparib. We propose that PARylation of BRCA1 is important to limit the formation of exces-sively extended DNA filaments, thereby reducing illegitimate chromosome rearrangements. Our results shed light on molecular aspects of HR and on the mechanisms of PARP inhibitor treatment.

PARylation of BRCA1 limits DNA break resection through BRCA2 and EXO1 / S. Lodovichi, R. Quadri, S. Sertic, A. Pellicioli. - In: CELL REPORTS. - ISSN 2211-1247. - 42:2(2023 Feb 28), pp. 112060.1-112060.14. [10.1016/j.celrep.2023.112060]

PARylation of BRCA1 limits DNA break resection through BRCA2 and EXO1

S. Sertic;A. Pellicioli
Ultimo
2023

Abstract

The nucleolytic processing (resection) of a DNA double-strand break (DSB) is a critical step to repair the lesion by homologous recombination (HR). PARylation, which is the attachment of poly(ADP-ribose) (PAR) units to specific targets by PAR polymerases (PARPs), regulates many steps of HR, including resection. Here, we show that preventing PARylation of the oncosuppressor BRCA1 induces hyper-resection of DSBs through BRCA2 and the EXO1 nuclease. Upon expression of the unPARylatable variant of BRCA1, we observe a reduced 53BP1-RIF1 barrier for resection accompanied by an increase in the recruitment of the RAD51 recombinase. Similar results are observed when cells are treated with the clinically approved PARP inhibitor olaparib. We propose that PARylation of BRCA1 is important to limit the formation of exces-sively extended DNA filaments, thereby reducing illegitimate chromosome rearrangements. Our results shed light on molecular aspects of HR and on the mechanisms of PARP inhibitor treatment.
53BP1 barrier; BRCA1/2; CP: Molecular biology; DNA repair; DSB resection; EXO1; PARP; olaparib
Settore BIO/11 - Biologia Molecolare
28-feb-2023
1-feb-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/967949
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